Premature Moustache As Presenting Symptom of Nonclassic Congenital Adrenal Hyperplasia due to 2 Uncommon Mutations of theCYP21A2Gene

Case Reports in Genetics ◽

10.1155/2011/913020 ◽

2011 ◽

Vol 2011 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Guy Massa ◽

Philippe Gillis ◽

Marianne Schwartz

Keyword(s):

Genetic Analysis ◽

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Gene Encoding ◽

Rare Mutations

A Turkish boy was referred at the age of 3 6/12 years for the evaluation of a premature moustache. No other signs of virilisation were present. The endocrine evaluation led to the diagnosis of nonclassic congenital adrenal hyperplasia. Genetic analysis revealed 2 rare mutations of theCYP21A2gene, the gene encoding for the 21-hydroxylase enzyme: a recently reported R132C mutation in exon 3 and a R339H mutation in exon 8, both reported in the nonclassic CAH. An early moustache, for which the term premature moustache can be coined, can be the presenting symptom of nonclassic CAH. In all children presenting with a sex or age inappropriate development of a moustache, an endocrine evaluation is indicated.

Download Full-text

Genetic analysis does not confirm non-classical congenital adrenal hyperplasia in more than a third of the women followed with this diagnosis

HORMONES ◽

10.14310/horm.2002.1509 ◽

2014 ◽

Author(s):

Valeria Alcantara-Aragon ◽

Silvia Martinez-Couselo ◽

Diana Tundidor-Rengel ◽

Susan Webb ◽

Gemma Carreras ◽

...

Keyword(s):

Genetic Analysis ◽

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia

Download Full-text

Prevalence of Nonclassic Congenital Adrenal Hyperplasia in Turkish Children Presenting with Premature Pubarche, Hirsutism, or Oligomenorrhoea

International Journal of Endocrinology ◽

10.1155/2014/768506 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Cigdem Binay ◽

Enver Simsek ◽

Oguz Cilingir ◽

Zafer Yuksel ◽

Ozden Kutlay ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Mutational Analysis ◽

Autosomal Recessive Disorder ◽

Adrenal Hyperplasia ◽

Acth Stimulation ◽

Gene Encoding ◽

Turkish Children ◽

17 Hydroxyprogesterone ◽

Ovarian Syndrome ◽

Premature Pubarche

Background. Nonclassic congenital adrenal hyperplasia (NCAH), caused by mutations in the gene encoding 21-hydroxylase, is a common autosomal recessive disorder. In the present work, our aim was to determine the prevalence of NCAH presenting as premature pubarche (PP), hirsutism, or polycystic ovarian syndrome (PCOS) and to evaluate the molecular spectrum ofCYP21A2mutations in NCAH patients.Methods. A total of 126 patients (122 females, 4 males) with PP, hirsutism, or PCOS were included in the present study. All patients underwent an ACTH stimulation test. NCAH was considered to be present when the stimulated 17-hydroxyprogesterone plasma level was >10 ng/mL.Results. Seventy-one of the 126 patients (56%) presented with PP, 29 (23%) with PCOS, and 26 (21%) with hirsutism. Six patients (4,7%) were diagnosed with NCAH based on mutational analysis. Four different mutations (Q318X, P30L, V281L, and P453S) were found in six NCAH patients. One patient with NCAH was a compound heterozygote for this mutation, and five were heterozygous.Conclusion. NCAH should be considered as a differential diagnosis in patients presenting with PP, hirsutism, and PCOS, especially in countries in which consanguineous marriages are prevalent.

Download Full-text

Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency*

Endocrine Reviews ◽

10.1210/edrv.21.3.0398 ◽

2000 ◽

Vol 21 (3) ◽

pp. 245-291 ◽

Cited By ~ 9

Author(s):

Perrin C. White ◽

Phyllis W. Speiser

Keyword(s):

Congenital Adrenal Hyperplasia ◽

External Genitalia ◽

Clinical Severity ◽

Sodium Balance ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Gene Encoding ◽

Salt Wasting ◽

Direct Mutation ◽

21 Hydroxylase Deficiency

Abstract More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal “salt wasting” crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions—transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

Download Full-text

Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia

Endocrine Connections ◽

10.1530/ec-14-0032 ◽

2014 ◽

Vol 3 (2) ◽

pp. 67-74 ◽

Cited By ~ 7

Author(s):

Ingeborg Brønstad ◽

Lars Breivik ◽

Paal Methlie ◽

Anette S B Wolff ◽

Eirik Bratland ◽

...

Keyword(s):

Enzyme Activity ◽

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Gene Encoding ◽

Salt Wasting ◽

Functional Studies ◽

Norwegian Population ◽

Liquid Chromatography Tandem Mass ◽

17 Hydroxyprogesterone

In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with CAH, of which p.L388R and p.E140K were associated with salt wasting (SW), p.P45L with simple virilising (SV) and p.V211M+p.V281L with SV to non-classical (NC) phenotypes. We aimed to characterise the novel variants functionally utilising a newly designed in vitro assay of 21OH enzyme activity and structural simulations and compare the results with clinical phenotypes. CYP21A2 mutations and variants were expressed in vitro. Enzyme activity was assayed by assessing the conversion of 17-hydroxyprogesterone to 11-deoxycortisol by liquid chromatography tandem mass spectroscopy. PyMOL 1.3 was used for structural simulations, and PolyPhen2 and PROVEAN for predicting the severity of the mutants. The CYP21A2 mutants, p.L388R and p.E140K, exhibited 1.1 and 11.3% of wt 21OH enzyme activity, respectively, in vitro. We could not detect any functional deficiency of the p.P45L variant in vitro; although prediction tools suggest p.P45L to be pathogenic. p.V211M displayed enzyme activity equivalent to the wt in vitro, which was supported by in silico analyses. We found good correlations between phenotype and the in vitro enzyme activities of the SW mutants, but not for the SV p.P45L variant. p.V211M might have a synergistic effect together with p.V281L, explaining a phenotype between SV and NC CAH.

Download Full-text

Mutations in CYP11B1 and Congenital Adrenal Hyperplasia in Moroccan Jews

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-1145 ◽

2005 ◽

Vol 90 (9) ◽

pp. 5463-5465 ◽

Cited By ~ 27

Author(s):

Tamar Paperna ◽

Ruth Gershoni-Baruch ◽

Kader Badarneh ◽

Leah Kasinetz ◽

Ze’ev Hochberg

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Founder Mutation ◽

Compound Heterozygote ◽

Single Mutation ◽

Carrier Rate ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Gene Encoding ◽

High Incidence ◽

Private Mutation

Abstract Context: In Jews of Moroccan descent (MJ), the prevalence of steroid 11β-hydroxylase deficiency (11-OHD) is relatively high, with a carrier rate estimated as approximately one in 40. A single mutation in the CYP11B1 gene (encoding 11β-hydroxylase), R448H, was suggested to account for the disease alleles in this population. Study Subjects: We screened 236 healthy MJ for R448H. Results: Only two of the subjects screened were found to be carriers, suggesting that the R448H allele frequency is lower than was assumed previously. An R448H/R448C compound heterozygote patient, diagnosed with 11-OHD, was identified. However, a subsequent screen of MJ subjects for R448C failed to detect any carriers, suggesting that this was a private mutation of this family. Conclusion: The high incidence of 11-OHD in MJ, therefore, is only partially explained by the presence of R448H as a founder mutation.

Download Full-text

ACQUISITION OF ALDOSTERONE BIOSYNTHETIC CAPACITY IN CONGENITAL ADRENAL HYPERPLASIA WITH HOMOZYGOUS DELETION OF THE GENE ENCODING P450/C21

Pediatric Research ◽

10.1203/00006450-198704010-00523 ◽

1987 ◽

Vol 21 (4) ◽

pp. 254A-254A

Author(s):

Phyllis W Speiser ◽

Perrin C White ◽

Maria I New

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Homozygous Deletion ◽

Adrenal Hyperplasia ◽

Gene Encoding

Download Full-text

HLA-LINKED CONGENITAL ADRENAL HYPERPLASIA RESULTS FROM A DEFECTIVE GENE ENCODING A CYTOCHROME P-450

Pediatric Research ◽

10.1203/00006450-198411000-00042 ◽

1984 ◽

Vol 18 (11) ◽

pp. 1208-1208 ◽

Cited By ~ 1

Author(s):

P C White ◽

M I New ◽

B O Dupont ◽

Sloan-Kettering

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Gene Encoding ◽

Defective Gene ◽

Cytochrome P 450

Download Full-text

Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: An Update on Genetic Analysis of CYP21A2 Gene

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1108-1419 ◽

2020 ◽

Author(s):

Berta Carvalho ◽

C.Joana Marques ◽

Rita Santos-Silva ◽

Manuel Fontoura ◽

Davide Carvalho ◽

...

Keyword(s):

Genetic Analysis ◽

Congenital Adrenal Hyperplasia ◽

Late Onset ◽

Molecular Genetic Analysis ◽

Clinical Severity ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Cyp21a2 Gene ◽

Pathogenic Variants ◽

21 Hydroxylase Deficiency

AbstractCongenital Adrenal Hyperplasia is a group of genetic autosomal recessive disorders that affects adrenal steroidogenesis in the adrenal cortex. One of the most common defects associated with Congenital Adrenal Hyperplasia is the deficiency of 21-hydroxylase enzyme, responsible for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. The impairment of cortisol and aldosterone production is directly related to the clinical form of the disease that ranges from classic or severe to non-classic or mild late onset. The deficiency of 21-hydroxylase enzyme results from pathogenic variants on CYP21A2 gene that, in the majority of the cases, compromise enzymatic activity and are strongly correlated with the clinical severity of the disease. Due to the exceptionally high homology and proximity between the gene and the pseudogene, more than 90% of pathogenic variants result from intergenic recombination. Around 75% are deleterious variants transferred from the pseudogene by gene conversion, during mitosis. About 20% are due to unequal crossing over during meiosis and lead to duplications or deletions on CYP21A2 gene. Molecular genetic analysis of CYP21A2 variants is of major importance for confirmation of clinical diagnosis, predicting prognosis and for an appropriate genetic counselling. In this review we will present an update on the genetic analysis of CYP21A2 gene variants in CAH patients performed in our department.

Download Full-text